The disclosure of each patent, patent application and publication cited or described in this document is hereby incorporated herein by reference, in its entirety.
Glaucoma is a condition of the eye that is made up of a collection of eye diseases that cause vision loss by damage to the optic nerve. Elevated intraocular pressure (IOP) due to inadequate ocular drainage is a primary cause of glaucoma. Glaucoma can develop as the eye ages, or it can occur as the result of an eye injury, inflammation, tumor, or in advanced cases of cataract or diabetes. It can also be caused by certain drugs, such as steroids. Glaucoma can develop in the absence of elevated IOP. This form of glaucoma has been associated with inheritance (i.e., family history of normal-tension glaucoma) Japanese ancestry, as well as systemic heart disease, such as irregular heartbeat.
There are two main anatomic classifications of glaucoma. These classifications are based on whether the angle of the anterior chamber is open or narrow. The more common open-angle glaucoma is a chronic disease, whereas the less common angle-closure glaucoma is an acute disease. Open-angle glaucoma is usually associated with an increase in intraocular pressure, resulting in damage to the optic nerve and the appearance of cupping of the optic disk. There is an increase in the cup-to-disk ratio and visual dysfunction in the midperipheral field of vision.
Conventional therapy for glaucoma has involved topical administration of pilocarpine and/or epinephrine, and more recently, beta-blockers administered to the eye several times daily. Various beta-blocking agents have been used to lower intraocular pressure. Such use is described, for example, in reviews by W. P. Boger in Drugs, 18, 25-32 (1979) and by T. J. Zimmerman and W. P. Boger in Survey Ophthalmol. 23(b), 347 (1979). U.S. Pat. No. 4,195,085 to Stone discloses a method for treatment of glaucoma by the ocular administration of a beta-blocking compound, timolol maleate. However, these methods also possess significant drawbacks, in that the absorption of the beta-blocking compound into the systemic circulation can cause undesirable, even life-threatening, side effects. Such side effects result from prolonged beta-blocking action on the heart, bronchioles and blood vessels. Accordingly, there is a need for compounds and a method of treatment of glaucoma or for lowering intraocular pressure that is relatively free of unwanted systemic side effects.
Certain beta-blocking agents that contain enzymatically labile ester groups are known to exhibit short-acting beta-blocking effects in the systemic circulation. Such short-acting beta-blocking compounds (SAABs) have been suggested for treatment or prophylaxis of cardiac disorders as a means for reducing heart work or improving rhythmicity for a short duration. Such short-acting beta-blocking compounds can avoid the sometimes counterproductive effects of conventional beta-blocking agents, whose effects are long-lived and, therefore, difficult to precisely control. Beta-blocking agents having such properties are described in Matier, et al., U.S. Pat. No. 4,402,974, Sep. 6, 1983; Matier, U.S. Pat. Nos. 4,454,154 and 4,455,317.
Topical eye-drops are the most common medical treatment of open-angle glaucoma. Meiotic agents, primarily parasympathetic (e.g., pilocarpine), constrict the pupil to enhance aqueous flow through the trabecular meshwork. The meiotic pupils, however, interfere with night vision. The carbonic anhydrase enzyme inhibitors (e.g., acetazolamide) are orally and topically administered agents (e.g., dorzolamide) that decrease the production of aqueous from the ciliary body, thereby reducing IOP. Recently introduced synthetic prostaglandin analogues (e.g., latanoprost) reduce intraocular pressure by increasing aqueous outflow.
Typically less than 1% of the topically instilled dose is absorbed (N. L. Burstein and J. A. Robinson, J. Ocular Pharmacol. 1, 309 (1985). Even at this low absorption, potent beta-blockers with longer durations of action can cause severe systemic side effects, particularly in patients who also suffer from cardiovascular or bronchosplastic disease. In an attempt to reduce or eliminate such side effects and enhance ocular penetration, several acyl-ester prodrugs of propanolamine-containing beta-blockers have been developed. See, e.g., Vincent, H. L. Lee, and Hans, Bundgaard, “Prodrugs”, Chapter 7, Marcel Dekker, Inc, Kenneth B. Sloan (ed.), 1992, p. 221; M. Shammem, T. Imai and M. Otagiri, J. Pharm. Pharmacol., 45, 246, 1993 (describing propranolol prodrugs); 246; Hans Bundgaard, Anders Buur, Shih-Chieh Chang and Vincent H. L. Lee, International Journal of Pharmaceutics, 77-88, 1988 (describing timolol prodrugs); C G Jordan, J. Pharm. Sci., 87 (7), 880-885, 1998 (describing oxprenolol prodrugs); Patil, et al., U.S. Pat. No. 4,897,417 issued Jan. 30, 1990; and Patil , et al., U.S. Pat. No. 4,966,914 issued Oct. 30, 1990, both discussed in greater detail below.
Among the beta-blocker prodrugs reported in the literature as anti-glaucoma agents, the most common acyl functionality studied is a pivaloyl ester derivative of the secondary hydroxyl group within the oxypropanolamine side chain of the beta-blockers. Interestingly, the physical and chemical characteristics of each pivaloyloxy beta-blocker prodrug are different. For example, the half-life of the oxprenolol prodrug
in phosphate buffer (pH 7.4) at 37° C. is 2035.5 days. Under identical conditions, the half-life of the timolol prodrug
and a compound of Patil , et al., U.S. Pat. No. 4,966,914 of the formula
are 3.6 hours and 0.9 hours respectively. These data suggest that the physical and chemical characteristics of an acyl beta-blocker prodrug cannot be predicted solely from the properties of structurally dissimilar yet similarly derivatized beta-blocker prodrugs.
The aforementioned compound disclosed in U.S. Pat. No.4,966,914 was reported to be an oculoselective beta-blocker having a long duration of action in the ocular fluid and a short duration of action in the systemic circulation. Because of the difference between their intraocular and systemic stabilities, the compound was suggested to provide enhanced intraocular pressure (IOP) reduction capabilities in the eye for extended periods while reducing the level of severe systemic side effects. Two compounds disclosed in U.S. Pat. Nos. 4,897,417 and 4,966,914 to Patil et al.,
are ester “prodrugs”, which are converted in vivo to the active agent of the 914 patent. The prodrugs and their active parent compound were evaluated for their beta-blocking actions, ocular bioavailability and their ocular or systemic safety in animal studies. Neither of the two prodrugs was found sufficient with respect to solution stability and ocular safety profile.
For treatments involving introduction of medicaments into the eye, an ideal beta-blocker prodrug would be stable in buffer solution for good shelf life, and would rapidly hydrolyze in the cornea to deliver the parent compound in the aqueous humor. The parent compound thus provided should be sufficiently stable in the aqueous humor to extend the duration of intraocular pressure lowering, devoid of ocular irritation and local anesthetic activity and rapidly eliminated from systemic circulation to reduce or eliminate systemic effects such as heart failure and bronchospasm. Finally, the prodrug compound should not bind to beta-receptors upon systemic absorption. It can be seen from the foregoing discussion that there is still a need for prodrug forms of beta-blocking agents, as well as novel beta-blocking agents themselves, that possess this combination of desirable features.